Gallbladder adenomyomatosis (GAM) is an acquired, reactive, tumor-like condition. Malignant transformation is extremely rare, and imaging features during contrast-enhanced ultrasound (CEUS) have not been described before. Herein, we describe a 73-year-old Asian man who had been diagnosed with gallbladder carcinoma by conventional ultrasonography (US). Based on additional radiological findings, we believed that it was a localized adenomyomatosis. However, the histopathological diagnosis was adenocarcinoma originate from adenomyomatosis with serosal invasion. We believe this is the first case of adenocarcinoma derived from GAM with characteristics of CEUS findings. This case is presented to indicate a clinical awareness of malignant transformation of GAM and discuss the radiology significance with an emphasis on CEUS.

Gallbladder adenomyomatosis (GAM) is a benign disease with prevalence among cholecystectomy specimens ranging from 2% to 5%. It is characterized by invaginations of the mucosa that penetrate a hypertrophied muscular wall and form the so-called Rokitansky-Aschoff sinuses (RAS). Whether or not GAM is a premalignant lesion has yet to be elucidated. However, after a review of associated literature, five cases about the malignant transformation of GAM have been reported. To our knowledge, our case is the first one with serosal invasion. Moreover, the contrast-enhanced ultrasound (CEUS) imaging characteristics have never been reported before.

> Case Report

A 73-year-old Asian man underwent US because of episodes of nausea without vomiting. Conventional ultrasonography (US) revealed a hypoechoic mass at the fundus of the gallbladder. For definitive diagnosis, he was referred to our hospital. The physical examination on admission was unremarkable. The patient had no history of surgery. Results of laboratory examinations, including levels of serum alpha-fetoprotein, carcinoembryonic antigen, and CA19-9, were within the normal range. Conventional US was performed using a scanner (LOGIQ 9 GE, GE Healthcare, Milwaukee, WI) equipped with a convex transducer (3.5–5 MHz). The US revealed a lesion located at the fundus of the gallbladder. The lesion was a hyperechoic solid mass with blurred boundaries and uneven surface. On color Doppler US, a few blood flow signals were seen inside the lesion [Figure 1]. After an intravenous injection of contrast agent (2.4 mL, SonoVue; Bracco, Milan, Italy) following by a 10 ml saline flush, the patient underwent CEUS with low acoustic power (mechanical index <0.2). Contrast-specific mode pulse sequencing was applied, which provides real-time scanning. Enhancement was assessed by comparison with the echogenicity of adjacent liver parenchyma. During the arterial phase, the wall of the gallbladder depicted as hyperenhanced, beginning at 24 s after injection of contrast agent, and an inhomogeneously hyperenhanced lesion (approximately 2.5 cm × 1.4 cm) with multiple nonenhancements at the fundus was seen. At 29 s, the continuity of the gallbladder wall beneath the lesion became obscured while the adjacent gallbladder wall appeared intact [Figure 2]. At 1 min 38 s during the venous phase, the entire lesion became hypoenhanced, and the interior areas of nonenhancement became more apparent. The ultrasonographer scanned the liver beginning 120 s after administration of contrast agent; no abnormally enhanced hepatic lesions were seen. A localized type GAM was not ruled out. The patients gave written informed consent after the procedure has been carefully explained to the patient.

Figure 1: On color Doppler US, a few blood flow signals were seen inside the lesion

The patient underwent laparoscopic cholecystectomy. The histopathological findings included dilated cystic structures characteristics of adenomyomatosis (RAS) with a stroma consisting of fibrous connective tissue and bundles of smooth muscle cells. The irregularly shaped glandular structures ranged from benign to malignant in appearance and extended beyond the hyperplastic muscular layer to invade the serosal layer [Figure 4], leading to the diagnosis of malignant transformation of adenomyomatosis with infiltration of the serosa. The patient did not receive other additional interventions, and there was no evidence of local recurrence or metastatic disease during 24 months of follow-up.

Figure 4: Micrograph imaging leading to the diagnosis of malignant transformation of adenomyomatosis with infiltration of the serosa (H and E, ×100)

GAM was defined as epithelial proliferation protruding into the muscular layer of and are considered to be the specific and classical diagnostic feature of GAM.[1],[2],[3] Thus far, the etiology, pathology, epidemiology of GAM remain unclear. The appropriate treatment for GAM has continued to be a dilemma.[4] Opinions on the malignant potential of GAM have varied. However, there has been some recent attention regarding its potential for malignant transformation.[5],[6],[7] To our knowledge, five cases [8],[9],[10],[11],[12][Table 1] on the malignant transformation of adenomyomatosis have been reported since 1986. In our review of the associated literature, we found that no recurrences or metastases were found during the follow-up (ranging from 2 months to 4 years). Only one patient [9] underwent additional exploratory surgery, which did not reveal any metastases. All the cases, the occurrences located at the fundus of the gallbladder except one case [8] occurred at locations in both the fundus and body of the gallbladder. Both Zhang [11] and Terada [12] pointed out that surgical intervention is appropriate for adenomyomatosis since a delay in surgical intervention increases the risk of malignant transformation.

As for diagnosis, US is a primary diagnostic modality for GAM, which is ascribed to its inherent superiority such as cost-effectiveness, easy manipulation, and repeatability. On the US, GAM mainly appears as localized or diffuse wall thickening with intramural cystic structures within the affected wall (RAS). However, achieving a definitive diagnosis by conventional US may be difficult because the imaging features of GAM are sometimes nonspecific and can mimic malignancy.[13],[14],[15] In addition, the fundal portion of the gallbladder and gallbladder wall intactness beneath the lesion cannot always be adequately visualized by conventional US, owing to poor spatial resolution in the near-field, and interference by intestinal gas. Therefore, the differential diagnosis between nonspecific GAM and gallbladder carcinoma, sometimes, is difficult to achieve by conventional US. It is a necessity to develop a new US technique to improve diagnosis for GAM when it is impossible for conventional US to facilitate accurate diagnosis between nonspecific GAM and malignancy.

CEUS, however, has overcome the limitations of conventional ultrasound and prompted a major breakthrough in the delineation of gallbladder diseases. The ability to differentiate gallbladder diseases and provide sufficient contrast has been verified by investigators.[16],[17],[18] In our case, GAM resembled carcinoma on conventional US, whereas the differences were obvious on CEUS. The dilated RAS, which is pathognomonic for GAM, were clearly identified by CEUS imaging. The nonaffected gallbladder wall enhanced normally. Except for the absence of gallbladder wall below the lesion, the enhancement pattern seen in our patient resembled typical cases of GAM.[19] Because not much is known about this rare condition, the possibility that serosal invasion could lead to destruction of the integrity of the gallbladder wall was not considered.

> Conclusion

We reported a patient with malignant transformation of a fundal adenomyomatosis that showed invasion of the serosa. The integrity of the gallbladder wall, which provides specific clues for differentiation, can be adequately visualized by CEUS. However, because imaging techniques cannot always provide an accurate diagnosis, maintaining awareness of the malignant potential of GAM is very important. A comprehensive preoperative diagnostic workup and histopathological examination of the surgical specimen may be needed for the patient with suspected GAM.

Acknowledgment

Xiao-Chen Shi collected patient's information, organized and wrote the manuscript; Shao-Shan Tang* dealt with the figures and manuscript writing; Wei Zhao examined the resected tumor and approved the final manuscript.